Abstract:
:In the nervous system, NMDA receptors (NMDARs) participate in neurotransmission and modulate the viability of neurons. In contrast, little is known about the role of NMDARs in pancreatic islets and the insulin-secreting beta cells whose functional impairment contributes to diabetes mellitus. Here we found that inhibition of NMDARs in mouse and human islets enhanced their glucose-stimulated insulin secretion (GSIS) and survival of islet cells. Further, NMDAR inhibition prolonged the amount of time that glucose-stimulated beta cells spent in a depolarized state with high cytosolic Ca(2+) concentrations. We also noticed that, in vivo, the NMDAR antagonist dextromethorphan (DXM) enhanced glucose tolerance in mice, and that in vitro dextrorphan, the main metabolite of DXM, amplified the stimulatory effect of exendin-4 on GSIS. In a mouse model of type 2 diabetes mellitus (T2DM), long-term treatment with DXM improved islet insulin content, islet cell mass and blood glucose control. Further, in a small clinical trial we found that individuals with T2DM treated with DXM showed enhanced serum insulin concentrations and glucose tolerance. Our data highlight the possibility that antagonists of NMDARs may provide a useful adjunct treatment for diabetes.
journal_name
Nat Medjournal_title
Nature medicineauthors
Marquard J,Otter S,Welters A,Stirban A,Fischer A,Eglinger J,Herebian D,Kletke O,Klemen MS,Stožer A,Wnendt S,Piemonti L,Köhler M,Ferrer J,Thorens B,Schliess F,Rupnik MS,Heise T,Berggren PO,Klöcker N,Meissner T,Madoi
10.1038/nm.3822subject
Has Abstractpub_date
2015-04-01 00:00:00pages
363-72issue
4eissn
1078-8956issn
1546-170Xpii
nm.3822journal_volume
21pub_type
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